Ion channel diseases

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

canal diseases, canalopathies, (e) channelopathy; (e) Channelopathies

Definition
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Ion channel diseases" are a heterogeneous group, predominantly hereditary, often autosomal-dominantly inherited, less frequently acquired diseases, which are based on defects in ion channels. Ion channelsare membrane-bound proteins that form selectively effective pores for sodium, chloride, potassium and calcium ions. The undisturbed physiological functionality of these ion channels is an important prerequisite for the undisturbed activity of muscles or the nervous system. Ion channels mediate the conversion of sensory stimuli and transmit this information via action potentials and synaptic transmission processes.

Mutations in genes that code for channel proteins lead to a changed "switching behaviour" of the ion channels. Increased or decreased openings of the membrane-bound channel proteins cause a pathological excitation potential of the affected tissue. The diagnosis should be confirmed by molecular genetic diagnostics

Classification
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Neurogenic and muscular ion channel diseases

  • Nocturnal autosomal dominant frontal lobe epilepsy (Steinlein et al 1995): CHRNA4 (20q)- gene encoding the a-4 segment of the ligand-directed neuronal nicotinic acetylcholine receptor.
  • Nocturnal autosomal dominant frontal lobe epilepsy (De Fusco et al 2000): CHRNB2 (1q)- gene encoding the b-2 sub-section of the nicotinic acetylcholine receptor.
  • Benign neonatal seizures (Singh et al 1998): KCNQ2 (20q) gene coding for the voltage-dependent potassium channel.
  • Benign neonatal seizures (Charkier et al 1998): KCNQ3 (8q) gene encoding the voltage-dependent potassium channel.
  • Generalized epilepsy and febrile convulsions (Wallace et al 1998): SCN1B (19q) gene coding for the b-1 and a-1 section of the voltage-dependent sodium neuronal channel.
  • Generalized epilepsy and febrile convulsions (Escayg et al 2000): SCN1A (2q) gene coding for the b-1 and a-1 portion of the sodium voltage-dependent neural channel.
  • Generalized epilepsy and febrile convulsions (Baulac et al 2001): GABRG2 (5q) gene coding for the g-2 portion of the GABA-A receptor.
  • Childhood febrile convulsions / absence epilepsy (Wallace et al 2001): GABRG2 (5q) gene coding for the g-2 portion of the GABA-A receptor.
  • Periventricular heterotopy (Fox et al 1998): Filamine (Xq28) Filamine gene.
  • Episodic ataxia with myokymia (EA-1): KCNA1. Gene coding for a potassium channel
  • Episodic ataxia (EA-2): KCNA1. Gene that codes for a calcium channel.
  • Hemiplegic migraine: CACNL1A4. Gene coding for a calcium channel.
  • Stratle disease (hypereception): GLTA1. Gene coding for the alpha1 subeion of the glycine receptor
  • Autosomal dominant deafness (DFNA 2) KCNQ4

Skeletal muscular ion channel diseases

  • Potassium-sensitive myotonia (hypokalemic periodic paralysis type I) SCN4A . gene encoding the alpha subunit of the sodium ion channel.
  • Paramyotonia congenita: SCN4A. Gene encoding the alpha subunit of the sodium ion channel.
  • Hyperkalemic myotonia: SCN4A. Gene encoding the alpha subunit of the sodium ion channel.
  • Hypokalemic periodic paralysis: CACNL1A3. Gene encoding calcium ion channel and dihydropyridine receptor.
  • A.R. (Becker) myotonia: CLCN1. Gene coding for a chloride ion channel
  • A.D. myotonia: CLCN1. Gene coding for a chloride ion channel
  • Malignant hypertension: RYR1, SCNA4; CACNL2A, CACNL1A3. Different genes
  • Central Core disease: RYR1. Gene coding for the calcium release channel (ryanodine receptor)
  • Congenital myasthenia syndrome: CHRNA1; CHRNB1, CHRNE. Rarely only 1-4% of all myasthenia forms

Cardiac ion channel diseases

  • Cardiac ion channel disease is based on mutations of ion channels and other functional proteins that can lead to bradycardic and tachycardic supraventricular arrhythmias, ventricular arrhythmias, syncope and sudden cardiac death. Cardiac ion channel diseases can be classified according to the function of the mutated proteins. For clinical routine, the classification according to clinical and ECG criteria is particularly important.
  • Long QT syndrome: KCNQ1- KCNQ2; SCN5A. Genes coding for the slow and fast potassium channel. The mutations are associated with loss of function. Furthermore, this clinical picture is based on mutations in the gene of the cardiac sodium channel with an increase in function ("gain of function").
  • Romano-WRD syndrome: LQTS1-6.
  • Jervell and Lange-Nelsen syndrome: KVLQT1, KCNQ1, KCNA8.
  • Andersen-Tavil syndrome: LQTS7 gene. Gene coding for potassium channels.
  • Short QT syndrome: KCNH1 gene; KCNQ1 gene KCNJ2 gene.
  • Brugada syndrome: SCN5 gene. Gene coding for a protein of a potassium channel.
  • catecholaminergic polymorphic ventricular tachycardia (CPVT): ryanodine receptor organ (RyR2) / calcisequestrin (CASQ2) gene. These genes encode the proteins that control the release of calcium from the sarcoplasmic reticulum. Patients with CPVT have a normal resting ECG and a structurally and functionally normal echo. Pathognomonic are polymorphic ventricular extrasystoles and bi-directional or polymorphic ventricular tachycardia (VT), which are detectable in exercise and long-term ECG and in loop recorders or under drug provocation with epinephrine or isoproterenol. Adrenergically mediated atrial tachycardias can also occur.

Nephrogenic ion channel diseases

  • DeToni-Debré-Fanconi syndrome: EHHADH. Gene coding for the enzyme of the same name in mitochodrial fatty acid metabolism. The enzyme deficiency leads to tubule dysfunction
  • Bartter syndrome (different variants I-V -SLC12A; KCNJ1, CLCNKB, BSND). These genes lead to disorders in Na and Ca ion channels in the renal tubules and thus to disorders of tubular renal function.
  • Liddle syndrome: Mutations in a constitutively active Na channel with increased Na reabsorption.
  • EAST syndrome (epilepsy, ataxia, hearing loss, tubulopathy): KCNJ10. Gene coding for a potassium channel which in kidneys is located here in the distal nephron, brain and the stria vascularis of the inner ear.

Other:

  • Cystic fibrosis (pleiotropic ion channel disease with substantial lung involvement): The monogenic disease cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Etiopathogenesis
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Nerves, muscle and sensory cells need a sufficient electrical charge state to fulfil their function (comparable to a battery). Ion channels provide for an electrical homeostasis of the cells. Genetic or autoimmunologically induced changes in the composition of the channel proteins can temporarily or permanently lead to a discharge of this "cell battery" and thus cause diseases. Changes in ion channels are associated with the following diseases:

  • Chloride channels: Disturbances of the chloride channels are responsible for Myotonia congenita Thomson and Myotonia congenita Becker.
  • Sodium channels: Disorders of the sodium channels are responsible for Eulenburg's paramyotonia congenita, myotonia fluctuans, myotonia permanent, acetazolamide sensitive myotonia and hyperkalemic periodic paralysis.
  • Potassium channels: Disturbances of the potassium channels are believed to be responsible for familial benign neonatal convulsions, episodic ataxia type 1, paroxysmal choreoathetosis, and a form of hereditary deafness.
  • Calcium channels: Disorders of calcium channels seem to be responsible for hypokalemic periodic paralysis, malignant hyperthermia, and central-core myopathy, congenital deafness (KCNQ4), and certain forms of night blindness. Schizophrenia is also suspected of having a dysfunction of KCNN3, a calcium-dependent potassium channel.
  • Autoimmunological channelopathies: Isaacs syndrome (acquired neuromyotonia) is an antibody-mediated potassium ion channel disease. The "target channel proteins of these antigens are so-called "voltage-gated potassium channels (VGKCs), especially dendrotoxin-sensitive fast potassium channels or the ganglionic nicotinic acetylcholine receptors (AChR). Here, the suppression of the outwardly directed potassium flow leads to hyperexcitability of the peripheral nerves.
  • Mutations in several ion channels: central nervous excitation disorders such as episodic ataxias, familial hemiplegic migraine and 3 forms of dominant hereditary epilepsies. There is evidence that some epilepsies are ion channel disorders. Various ion channels can be affected (potassium, sodium and calcium channels). In the group of idiopathic-generalised epilepsies, an interaction of different genes seems to occur.

Pathophysiology
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Ion channels are membrane proteins that form selective pores for Na+, K+, Cl- or Ca2+ ions. They are the basis of the electrical excitability of nerve and muscle cells. Ion channels mediate communication with the environment by transforming different stimuli into receptor potentials. At muscular effector organs such as heart or skeletal muscle, they convert the electrical action potential into a mechanical muscle contraction. In the transmission of the action potential, it is the electrical membrane voltage that controls the switching behaviour of sodium and potassium channels via specific conformational changes of the proteins; in synaptic transmission processes, it is ligands such as acetylcholine and its receptors that transmit information.

Clinical features
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Ion channel diseases are clinically characterized by an episodic occurrence of various functional disorders of the skeletal or cardiac muscles and the central nervous system (more rarely other tissues, e.g. the kidney). During a seizure there is usually an involuntary disturbance of excitation of the affected tissue. Depending on the type and location of the ion channel, this can manifest itself as cardiac arrhythmia, muscle stiffness, paralysis, ataxia, migraine or epileptic seizures. In organs that are not primarily excitable, such as the kidney, mutations in ion channels can cause electrolyte disorders.

Often the symptoms can be provoked by certain triggers, such as physical exertion or intake of carbohydrate-rich food. In the seizure-free interval, patients are often inconspicuous. However, in the course of some diseases, degeneration of the affected tissue may develop, leading to slowly progressive muscle atrophies, ataxia or nystagmus, for example.

Diagnosis
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The family history plays a key role in the analysis of an ion channel disease.

If a genetic defect is known, the pathophysiology of ion channel diseases can be elucidated in detail using electrophysiological techniques (voltage clamp, patch clamp - see below ion channels), which allow an exact functional analysis of the mutated ion channels down to the molecular level.

In clinically identified familial syndromes with typically episodic central or peripheral excitation disorders, such as epileptic seizures, episodic ataxias, paroxysmal dystonia or migraine, cardiac arrhythmia, the disease is additionally confirmed by molecular genetic investigations.

Therapy
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Treatment can also be based on the knowledge of the pathophysiological mechanism. Drugs, changes in the concentration of the ions can alter the threshold of activation of the ion channels or inactivate them, an action potential and the transmission of a nerve impulse is thus either facilitated or prevented.

Note(s)
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Due to the fundamental importance of ion channels, it would actually be expected that mutations in these highly conserved and functionally important regions with changes in specific proteins would not allow for viability. Often, however, the measurable changes in the switching behaviour of the sodium channel are only very small and lead to only minor disturbance over a long period of time. Only when an additional trigger is added, e.g. a membrane depolarization due to an increase in potassium in the serum after muscle work, can the system become unbalanced. The disturbance becomes clinically manifest.

Literature
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  1. Cannon SC (2018) Sodium channelelopathies of skeletal muscle. Handb Exp Pharmacol 246:309-330.
  2. Cooper EC et al (2000) Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. PNAS 97: 4914 - 4919.
  3. Dedek K et al (2001) Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. PNAS 98: 12272 - 12277.
  4. Horn FL (2002) Ion channel diseases -general characteristics and pathomechanisms Dt Ärztebl 97: A-1826–1831
  5. Kullmann DM (2002) The neuronal channelopathies. Brain 125: 1177 - 1195.
  6. Priori SG et al(2003) Risk with the Long-QT Syndrome Risk influenced by genotype and duration of the QT. NEJM 348:1866-1874
  7. Schwartz PJ et al (2001) Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 103:89-95.
  8. Shieh CC et al (2000) Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities. Pharmacol Rev 52: 557 - 594.
  9. Takenaka K et al (2003) Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome Circulation 107: 838 - 844.
  10. Vaeth M et al (2018) Ion channelopathies of the immune system. Curr Opin Immunol 52:39-50.

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Last updated on: 29.10.2020